Subclinical Cushing’s

Syndrome
AACE 26th Annual Scientific & Clinical Congress
Associate Clinical Professor of Medicine and Clinical Chief
University of Miami Miller Scholl of Medicine
Miami, Florida
aayala2@miami.edu

Austin, Texas
May of 2017
 Objectives

• Review the concept of “Subclinical”

Cushing’s Syndrome (SCS)

• Establish a diagnostic and therapeutic

approach, consider biases

• Discuss future directions

 Full-blown Cushing’s Syndrome
(CS)
• UFC > 4 x normal

• Lack of dexamethasone suppression

• Loss of cortisol diurnal rhythm

 Clinical features of Cushing’s syndrome
Clinical Feature Sens Spec Clinical Feature Sens Spec

Increased fatigue 100 Glucose intolerance

Decreased libido 33-100 Difficult to control HTN

Recurrent infections 14-25

Weight gain 79-97
Plethora 78-94 69
Irritability 40-86
Round Face 88-92
Insomnia 69 Hirsutism 64-84 61
Decreased concentration 66 Hypertension 74-90 83
Eccymoses 60-68 94
Impaired short-term 83 Striae wider than 1 cm 50-64 78
memory and purple in color
Weakness 56-90 93
Changes in appetite 54
Abnormal fat distribution 34-67
Lethargy, depression 40-67

Edema 48-66 83
Menstrual changes 35-86 49
Abdominal pain 21
Osteopenia 48-83 94
Acne 21-82 76
Headache 47-58 63
Female Balding 13-51
Backache 39-83 Thin skin 84
 Endocrine Testing: CS
SCREENING

• Urine cortisol (UFC, by High Pressure Liquid

Chromatography)

• Bedtime salivary cortisol (Sal F)

Sal F, by radioimmunoassay (RIA)
Tandem mass spectrophotometry

• 1 mg dexamethasone suppression test (DST)

 Urine Free Cortisol

1000
UFC (nmol/d)

750

500

250

Cushing’s Pseudo-
Disease Cushing’s State

Yanovski, JA. JAMA 269:2232-8, 1993

Nighttime salivary cortisol (ug/dL)
Nighttime Salivary Cortisol
30
29
4.5 ♦ - healthy volunteer
▲ - control patient
4.0 ● - PseudoCushing State
● - Cushing’s Syndrome
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Outpatients Inpatients
Papanicolaou et al. JCEM 87:4515-21,2002
 SCS: Why is it difficult?

• The Definition

• The Confounding Comorbidities

• The Limitations of the Assays/Test

• The Clinical Relevance

• The Biases
 CASE
A 59 year-old woman
• Referred for further evaluation of an adrenal mass that was
discovered after she underwent abdominal CT to investigate
abdominal pain

• The mass measures 1.8 x 2.5 cm and has a density of -10

Hounsfield units without contrast. The patient has a history
of hypertension treated with hydrochlorothiazide. Other
medications: Aspirin

• On physical examination, BMI 35. Currently normotensive

• She has prediabetes and light pink abdominal striae. Reports

easy bruising.
9
 Laboratory test results:

Glucose = 121mg/dL (7.8 mmol/L) (reference range, 70-99 mg/dL [3.9-5.5

mmol/L])

Plasma renin activity = 3.5 ng/mL per h (reference range, 0.6-4.3 ng/mL per
h)

Aldosterone = 17 ng/dL (471.6 pmol/L) (reference range, 1-21 ng/dL [27.7-

285.5 pmol/L])

ACTH = 12 pg/mL (2.6 pmol/L) (reference range, 10-60 pg/mL [2.2-13.2

pmol/L])

DHEA-S = 5 µg/dL (0.14 µmol/L) (reference range, 15-157 µg/dL [0.41-4.25

µmol/L])

Serum cortisol (8 AM; 1-mg overnight dexamethasone suppression test) =

5.4 µg/dL (150.0 nmol/L) (reference range, <1.8 µg/dL [<49.7 nmol/L])

Urinary cortisol = 68 µg/24 h (187.7 nmol/L) (reference range, 4-50 µg/24 h

[11-138 nmol/d])
10

Normal Metanephrines in serum

The Definition (?)
 When Do We Consider SCS?

Evaluation of the HPA

axis is abnormal
 How Frequent Is It?

• ???? Depends on the definition

• Random cortisol
• Loss of circadian rhythm
• Blunted ACTH response to CRH
• Elevated UFC
• Abnormal Dexamethasone suppression
test (varying doses)
• Altered circadian cortisol rhythm
The Confounding Comorbidities
 Difficulty in Diagnosis
• Prevalence of incidentalomas increased (3-7 %) on CT
scanning

• Prevalence of obesity increased

• Prevalence of Osteoporosis is high (dependent of sex,

age)

• Prevalence of hypertension is close to 30 to 65 %

• Prevalence of Type II DM is 10 to 25 %
 Cushing’s Syndrome and Obesity

• In the obese population the prevalence of

Cushing’s syndrome is low

• Broad screening programs or having a low

threshold to screen obese patients is likely
not warranted

• Abnormal results should consider the

possibility of a false positive test
Journal of Clinical Endocrinology & Metabolism,
May 2008, 93(5):
The Laboratory Tests
What is the Differential Diagnosis of
Hypercortisolism?

What does the workup include?

 Alterations in HPA axis in patient with
SCS
• Debate on clinical/biochemical criteria for diagnosis

• No clinical “gold standard” parameter for diagnosis; thus expertise

dependent

• Diagnosis made on at least two altered parameters; needs to be

validated!!
• 1-mg overnight DST: mostly used for screening
• NIH/AACE/AAES: 5 mcg/dL as cutoff of normal level of
cortisol suppression
• French Society of Endocrinology use lower cutoff (1.8 mcg/dL)
• Grey area: cortisol between 1.8 and 5 mcg/dL ; interpret in
context of the clinical data
• A study showed that the 8mg DST no better at diagnosing SH
compared to 1mg DST.
• 2 day low dose DST proposed to be more accurate; no
definitive evidence showing its superiority.
 SCS: Endocrine Testing in
Suspected Cushing’s Syndrome
1-mg overnight dexamethasone suppression test (DST)

• To verify if there is loss of glucocorticoid negative feedback

• Cutoff:
• <1.8 ug/dL (higher sensitivity/lower specificity) vs. <5 ug/dL
• >14.3 ug/dL cortisol value  confirms CS

• False (+) 30-58% of patients with depression, schizophrenia, dementia,

OCD, alcoholism in the context of old age, weight loss, sleep deprivation,
medications, elevated CBG

• False (-) in nephrotic patients (lower CBG), liver/renal failure (decreased

dexamethasone clearance
vs.
Low dose 2 day DST:
• 2mg/day for 48hrs
• Better specificity but more cumbersome
• If there is 30% or more of cortisol suppression  no need to perform
HDDST
 Urine Cortisol
24 hr. urine cortisol (urinary free cortisol)
• High performance liquid chromatography, tandem mass
spectrometry, gas chromatography coupled with mass
spectrometry

• Measure 24hr urine creatinine (~20mg/kg LBW)

• Obtain a minimum of 2 samples r/out periodic hypercortisolism

• False (+): pseudo-Cushing states, OSA, PCOS, familial

glucocorticoid resistance, hyperthyroidism

• False (-): renal failure (GFR< 30 ml/min) & incomplete collection

• 1-4x ULN r/out pseudo-Cushing

• >4x ULN  Cushing's

ACTH level low (<5 pg/dL)

 Proceed with an adrenal imaging

o CT is preferred
o inhomogeneous mass
o >10 HU
o bilateral vs unilateral

o MRI help to distinguish adrenal adenoma from

nonfunctioning or metastatic tumor

o Variable, poor reproducibility (inter and intra assay)

 Alterations in HPA axis in SCS

• 24hr UFC
• By itself not adequate screening tool for SH due to its low
sensitivity.
• Circadian cortisol rhythm
• Studies reported that the MSC was not able distinguish
normal from SH
• Serum ACTH:
• not very sensitive
• patient with ACTH independent hypercortisolism might
have normal ACTH levels

• Low DHEAS

• Currently most clinicians are diagnosing on basis of: DST +

UFC+ ACTH
 Treatment of SCS
• Main goal  correct metabolic consequences

• No good quality prospective randomized trial available to compare

surgical vs. conservative approach

• A small prospective randomized trial  surgical treatment was

better at improving HTN, DM and obesity when compared to
conservative therapy

• A retrospective trial by Chiodini et al. showed that BP and glucose levels

improved s/p adrenalectomy in both patients with and without subclinical
Cushings.

• Consider surgery in young patients that have vascular, metabolic and/or

bone disorders that are deteriorating.

• Follow up for patient with conservative therapy:

• No specific guidelines have been accepted

• Expert recommendations to perform annual screening for first 5yrs with
• UFC, 1-mg DSGT and ACTH level
• Monitor for worsening of DM, HTN and BMD (retrospective studies)
Adrenalectomy in patients with adrenal tumors and subclinical Cushing’s
syndrome

Irina Bancos et al. Eur J Endocrinol 2016;175:R283-R295

Adrenalectomy vs conservative management in patients with subclinical Cushing’s
syndrome: Dichotomous outcomes.

Irina Bancos et al. Eur J Endocrinol 2016;175:R283-R295

Adrenalectomy vs conservative management in patients with subclinical Cushing’s
syndrome: Continuous outcomes.

Irina Bancos et al. Eur J Endocrinol 2016;175:R283-R295

Cortisol as a Marker for Increased Mortality in Patients
with Incidental Adrenocortical Adenomas

J Clin Endocrinol Metab. 2014 Dec; 99(12): 4462–

4470.
The Biases
 Spectrum Bias

• “Spectrum bias refers to the phenomenon

that the performance of a diagnostic test
may vary in different clinical settings
because each setting has a different mix
of patients”
 Spectrum Bias
100

Sensitivity (%)
50
men
women

0
0 50 100
100-Specificity (%)
 Spectrum

Setting
Inpatient
Health Community OutpatientC Tertiary Research ICU
Fair Clinic linic Facility
Hospital

Demographics
Caucasian Hispanic African Native Asian
American American

Clinical stage
Pseudo Severe
Normal Mild Moderate
Cushing’
s
 Verification Bias
• “When the results of a diagnostic test affect whether the gold
standard procedure is used to verify the test result, verification bias
is introduced.”

• Also called work up bias or referral bias.

• “Verification bias is common because many gold standard

procedures (i.e adrenlectomy in SCH), such as biopsy, surgery, and
angiography, are invasive, risky, and expensive.

• “Under these conditions, physicians are reluctant to refer patients

for the gold standard procedure, and patients are reluctant to
undergo the gold standard procedure, unless preliminary diagnostic
tests have positive results”

• If the preliminary diagnostic test (i.e 1 mg Dex) has a high false

positive rate….it is a problem!
Case (Cont.)
Our Patient: Repeat Evaluation
 Multiple UFC:
• 82171mcg/24hrs
 1mg DST:
• Cortisol level: 5.2 ug/dL
 11pm salivary cortisol level
• 0.09 mcg (normal is <0.09)
 ACTH:
• 10 pg/mL
 ASSESMENT & PLAN :

• 1.2 cm lipid rich adrenal tumor likely benign

adrenal adenoma

• Moderate elevation of 24hrs UFC + mild elevation

of midnight salivary cortisol + failed to suppress
1mg DST =
Dx: likely mild Cushing syndrome

• Follow up with repeat 24hr UFC and ACTH in light

that there are no typical cushinoid features,
except mild hypertension.
 Conclusions
• The diagnosis of SCS is limited by the diagnostic
performance of screening test

• Symptoms and signs that may be present in SCS are

common in highly prevalent disorders

• Verification and Spectrum Bias affect our ability to

better understand the benefits of surgery vs. watchful
waiting

• Unilateral adrenalectomy may be curative in select

cases but the lack means to identify those patients who
would most benefit from the procedure
 Thank You
Thank You